A novel cancer immunotherapy shows early promise in preclinical studies

Dr. Zihai Li and researcher Alessandra Metelli say GARP suppression adds to established cancer immunotherapies that also use antibodies.

A study, published in a recent issue of Cancer Research, identified a protein that could be a novel diagnostic marker that, targeted with an antibody, could be a new immunotherapy treatment to potentially help breast, colon and lung cancer patients.

The study found that the protein GARP, which helps breast cancer tumors grow and spread, could be a novel diagnostic marker for cancer and that targeting it with an antibody prevented metastasis to the lungs in a mouse model of breast cancer, report scientists at the Medical University of South Carolina.

The study found that the antibody, a protein used by the immune system to neutralize viruses and other harmful substances that can enter the body, could be used to successfully neutralize GARP, which then prevented breast cancer from spreading to the lungs. The researchers are now trying to figure out how to take their new treatment beyond the laboratory so that it can be used to help people with breast cancer and many other types of cancer.

Knowing how to target GARP, a TGF-beta cell surface receptor that helps breast cancer tumors grow and spread with an antibody, is a novel addition to established immunotherapies that wake up the immune system so that it can fight cancer, said Zihai Li, M.D., Ph.D., a leading cancer immunotherapist.

The antibody-based therapy targets the functions of TGF-beta that cause cancer where it is particularly dangerous, docked on the surface of tumor cells.

The work started by considering how TGF-beta grows out of control in the first place, said Li, chairman of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and principal investigator on the project. “TGF-beta is an old story. The new spin is that there is a docking receptor for TGF-beta which increases the activity of the cytokine, and this molecule is called GARP,” said Li.

TGF-beta is a cytokine, or secreted protein, that controls the cell cycle and is used by regulatory T cells (Tregs) as a signal to tell immune cells not to attack normal cells in the body. However, TGF-beta has become a widely studied cancer cytokine. Malignant tumors release large amounts of TGF-beta, which allows cancer cells to divide rapidly and push Tregs to suppress immune cells that fight them. It has been difficult to design therapies that block TGF-beta, mainly because healthy cells cannot function without it.

Enter GARP, the only known receptor that allows TGF-beta to dock on the surface of cells. In this way, GARP helps cells to store TGF-beta. Importantly, Li knew that GARP could bind and activate TGF-beta and then float off the surface of cells that express it. Could this be a way that cancer cells store and release TGF-beta?

The Li lab set to find out.

Alessandra Metelli is a member of Dr. Zihai Li's lab in the Department of Microbiology and Immunology.

Li and his colleagues, including first author and student Alessandra Metelli, reported in the study that levels of GARP were much higher in biopsies of human breast, lung and colon tumors than in normal tissue. With this finding, it was reasonable to hypothesize that higher levels of GARP molecules could be storing the TGF-beta needed for enhanced tumor growth.

To examine if GARP had a direct role in cancer development, they deleted the gene for GARP from mice with mammary tumors and found that, without GARP, breast cancer tumors grew slower and were less able to metastasize to the lungs. Further experiments showed increased TGF-beta signaling, tumor growth, and metastasis after the gene for GARP was inserted into mouse mammary tumor cells expressing high levels of GARP. Mice with more GARP also had more TGF-beta-releasing Treg cells. This meant that GARP helped breast cancer spread directly by raising TGF-beta levels, and indirectly by using Tregs to suppress the immune system's normal response to fight cancer cells.

When the GARP antibody was combined with standard chemotherapy, the tumors not only did not spread, but also shrank, meaning that a similar combination might boost the effectiveness of standard chemotherapy in breast cancer.

Blocking GARP might also inhibit the natural ability of Tregs to suppress the immune system, which could potentially lead to inflammatory autoimmune reactions. “Clinically some of the proven immunotherapies do induce some degree of autoimmunity,” he said. “When cancer is cured and patients stop immunotherapy, the autoimmune manifestations completely disappear as well.”

An accurate biomarker for GARP could offer an opportunity for earlier detection of other aggressive cancers, given that GARP levels increase before metastasis, according to Li. As part of their work, the group also showed that life expectancy was decreased in patients with colon or lung cancer whose biopsied tissues showed high levels of GARP. The challenge resides in the development of an antibody accurate enough to detect it in humans with cancer.

There have been great advances in cancer immunotherapies in the last decade, but there is still vast room for improvement. GARP suppression represents a novel addition to established cancer immunotherapies that also use antibodies to wake up the immune system to fight cancer. “This discovery is fundamentally important to how TGF-beta utilizes GARP to promote cancer and down-regulate the immune system, but it also creates an opportunity for both diagnostics and therapeutics,” said Li.